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NM_001042545.2(LTBP4):c.56_67dup (p.Leu19_Gln22dup) AND not specified

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jan 16, 2024
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000602424.6

Allele description [Variation Report for NM_001042545.2(LTBP4):c.56_67dup (p.Leu19_Gln22dup)]

NM_001042545.2(LTBP4):c.56_67dup (p.Leu19_Gln22dup)

Genes:
LOC130064472:ATAC-STARR-seq lymphoblastoid silent region 10636 [Gene]
LTBP4:latent transforming growth factor beta binding protein 4 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
19q13.2
Genomic location:
Preferred name:
NM_001042545.2(LTBP4):c.56_67dup (p.Leu19_Gln22dup)
HGVS:
  • NC_000019.10:g.40601443_40601454dup
  • NG_021201.1:g.13278_13289dup
  • NM_001042544.1:c.451+1266_451+1277dup
  • NM_001042545.2:c.56_67dupMANE SELECT
  • NM_003573.2:c.340+1266_340+1277dup
  • NP_001036010.1:p.Leu19_Gln22dup
  • NC_000019.9:g.41107349_41107360dup
  • NC_000019.9:g.41107360_41107361insTAGGGCCGCAGC
  • NM_001042545.1:c.56_67dup
  • NM_003573.2:c.340+1266_340+1277dup12
  • p.Gln22_Pro23insLeuGlyProGln
Links:
dbSNP: rs1220133830
NCBI 1000 Genomes Browser:
rs1220133830
Molecular consequence:
  • NM_001042545.2:c.56_67dup - inframe_insertion - [Sequence Ontology: SO:0001821]
  • NM_001042544.1:c.451+1266_451+1277dup - intron variant - [Sequence Ontology: SO:0001627]
  • NM_003573.2:c.340+1266_340+1277dup - intron variant - [Sequence Ontology: SO:0001627]
Observations:
1

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000731435Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Uncertain significance
(Mar 6, 2017) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004803462Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Likely benign
(Jan 16, 2024) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000731435.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

The p.Leu19_Gln22dup variant in LTBP4 has not been previously reported in indivi duals with pulmonary disease. Data from large population studies is insufficient to assess the frequency of this variant. This variant is a duplication of 4 ami no acids at positions 19-22 and is not predicted to alter the protein reading-fr ame. It is unclear if this duplication will impact the protein. In summary, the clinical significance of the p.Leu19_Gln22dup variant is uncertain.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004803462.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Variant summary: LTBP4 (NM_003573.2) c.340+1266_340+1277dup12 is located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. In addition, the variant is located to the first exon of an alternative transcript, where it is predicted to result in an in-frame duplication change (i.e. NM_001042545.2 c.56_67dup p.(Leu19_Gln22dup)). The variant allele was found at a frequency of 0.00023 in 1,452,510 control chromosomes, predominantly at a frequency of 0.00062 within the Finnish subpopulation in the gnomAD database (v4 dataset). However in certain European subpopulations the variant is reported with even higher allele frequencies, e.g. in the Estonians (i.e. 8/4648 alleles; AF: 0.001721), suggesting that the variant is likely a benign polymorphism. To our knowledge, no occurrence of c.340+1266_340+1277dup12 in individuals affected with Cutis Laxa - LTBP4 Related and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 517252). Based on the evidence outlined above, the variant was classified as likely benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2024